title: MicroRNA-mediated downregulation of mTOR/FGFR3 controls tumor growth induced by Src-related oncogenic pathways.
abstract: The tyrosine kinase c-Src is upregulated in various human cancers, but the molecular mechanisms underlying c-Src-mediated tumor growth remain unclear. Here we examined the involvement of microRNAs in the c-Src-mediated tumor growth. Microarray profiling revealed that c-Src activation downregulates a limited set of microRNAs, including miR-99a, which targets oncogenic mammalian target of rapamycin (mTOR) and fibroblast growth factor receptor 3 (FGFR3). Re-expression of miR-99a suppressed tumor growth of c-Src-transformed cells, and this effect was restored by the overexpression of mTOR. The downregulation of miR-99a was also observed in epidermal growth factor- and Ras-transformed cells, and it was suppressed by inhibiting the mitogen-activated protein kinase (MAPK) pathway. Furthermore, miR-99a downregulation is associated with mTOR/FGFR3 upregulation in various human lung cancer cells/tissues. The tumorigenicity of these cells was suppressed by the introduction of miR-99a. These findings suggest that the miR-99a-mTOR/FGFR3 pathway is crucial for controlling tumor growth in a wide range of human cancers that harbor upregulation of the Src-related oncogenic pathways.
authors.affiliation: Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan. coneyama@biken.osaka-u.ac.jp
authors.forename: C
authors.initials: C
authors.lastname: Oneyama
authors.forename: J
authors.initials: J
authors.lastname: Ikeda
authors.forename: D
authors.initials: D
authors.lastname: Okuzaki
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: T
authors.initials: T
authors.lastname: Kanou
authors.forename: Y
authors.initials: Y
authors.lastname: Shintani
authors.forename: E
authors.initials: E
authors.lastname: Morii
authors.forename: M
authors.initials: M
authors.lastname: Okumura
authors.forename: K
authors.initials: K
authors.lastname: Aozasa
authors.forename: M
authors.initials: M
authors.lastname: Okada
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D016000:Cluster Analysis; D015536:Down-Regulation; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: C561679:MIRN99 microRNA, human; D035683:MicroRNAs; C115711:PD 173074; D011743:Pyrimidines; D051498:Receptor, Fibroblast Growth Factor, Type 3; D019061:src-Family Kinases; D058570:TOR Serine-Threonine Kinases